The colony stimulating factors are a class of protein hormones that stimulate the proliferation and the function of specific blood cell types such as granulocytes. Granulocytes engulf and devour microbial invaders and cell debris and thus are crucial to infection response. Granulocytes have only a 6–12 hour life span in the bloodstream and are destroyed as they function. Accordingly, it necessary for the blood marrow stem cells to rapidly and constantly generate granulocytes. Granulocyte colony stimulating factor (G-CSF) is a protein that is essential for the proliferation and differentiation of granulocytes, particularly neutrophils.
However, as a result of their fast turnover, the granulocyte count falls rapidly and markedly upon bone marrow damage, for example from treatment with traditional cancer treatments, including chemotherapeutic agents and radiation, or immunologic disorders including AIDS. Accordingly, treatment with hG-CSF has been shown to be efficacious in minimizing some of the side effects of cancer therapies, as well as in treatment of suppressed immune systems.
However, wild-type hG-CSF has several disadvantages, including storage stability problems as well as a short half-life in the blood stream.
To this end, variants of G-CSF are known; see for example U.S. Pat. Nos. 5,214,132; 5,399,345; 5,790,421; 5,581,476; 4,999,291; 4,810,643; 4,833,127; 5,218,092; 5,362,853; 5,830,705; 5,580,755; 5,399,345 and 5,416,195 and references cited therein.
However, a need still exists for proteins exhibiting both significant stability and granulopoietic activity. Accordingly, it is an object of the invention to provide granulopoietic activity (GPA) proteins, nucleic acids and antibodies for the treatment of neutrophil disorders.